Gadolinium texaphyrins

Rosenthal, D.I. et al. (1999) A phase I single-dose trial of gadolinium texaphyrin (Gd-Tex), a tumor selective radiation sensitizer detectable by magnetic resonance imaging, Clin. Cancer Res. 5, 739-745. 

Anonymous (2004) Motexafin gadolinium gadolinium (III) texaphyrin, gadolinium texaphyrin, Gd-Tex, GdT2B2, PCI 0120, Drugs in R D 5, 52-57. 

Rosenthal, D.I. et al. (2000) Reversible renal toxicity resulting from high single doses of the new radiosensitizer gadolinium texaphyrin, Department of Radiation Oncology, University of Pennsylvania Medical Center, Philadelphia 19104-4283, USA, 593-598. 

Viala, J. et al. (1999) Phases IB and II multidose trial of gadolinium texaphyrin, a radiation sensitizer detectable at MR imaging preliminary results in brain metastases, Radiology 212, 755-759. 

Gadolinium texaphyrin (Gd-tex Figure 4.8) is reported to be an effective radiation sensitizer for tumour cells, whilst the corresponding lutetium compound, which absorbs light in the far-red end of the visible spectrum, is in Phase II trials for photodynamic therapy for brain tumours and breast cancer. 

Figure 3 Single crystal X-ray diffraction structure of the gadolinium texaphyrin complex PCI-0101 (2) (bis-nitrate form) showing the planar nature of the basic monoanionic texaphyrin macrocycle and the four putative inner sphere coordination sites for water (occupied by two apical methanol molecules and a bidentate nitrate anion in this structure). The Gd(III) ion is nine-coordinate and lies 0.60 A out of the plane through the five nitrogen atoms of the macrocycle. Most hydrogen atoms have been omitted for clarity. Thermal ellipsoids have been scaled to the 30% probability level. Reproduced from [22] with permission. 1993 American Chemical Society...

Figure 5 These MRI scans show a large lung cancer that was imaged before (A) and after (B) intravenous administration of gadolinium texaphyrin PCI-0120 (3) to a patient in the Pharmacyclics, Inc. sponsored Phase I clinical trial. PCI-0120 localizes in the tumor, producing a whitening of the tumor image (B)...

In recent clinical and preclinical work, researchers at Pharmacyclics Inc., have demonstrated that texaphyrins selectively localize in atheromatous plaque and not in the normal aortic wall [243,300,301]. In the case of gadolinium texaphyrin PCI-0120 (3), this has been shown in human populations via MRl. With lutetium texaphyrin PCI-0123 (4), spectral bioimaging of intact rabbit aortas (i.e. after PCI-0123 injection and subsequent sacrifice) served to reveal plaque-to-normal vessel retention ratios on the order of 34 to 1 [300]. Further, extensive preclinical studies have helped establish that PCI-0123 (4) may be used in a PDT sense to effect selective photodamage of atheromatous plaque lesions in diet-induced hypercholes-terolemic New Zealand white rabbits [243,300,301]. For instance, Woodbum et al. reported that a protocol involving i.v. injection of PCI-0123 (lOpmolkg per day... 

Even more important is the gadolinium texaphyrin (coded PCl-0120). The central metal atom is gadolinium(III). It is a very effective radiation sensitiz-... 

Figure 1.17 The texaphyrin-gadolinium chelate structure used as a photosensitizer and MRI contrast agent in the detection and treatment of cancer.

A water-solubilized texaphyrin based on gadolinium(III) (XCYTRIN ) is under current testing in a new Phase III clinical trial with the role to enhance the effects of radiation therapy for... 

Another approach has been tackled with by Sessler et al. [37, 38] who described gadolinium(III) complexes with texaphyrins as potential MRI contrast agents. When the expanded porphyrin ring is subtituted by water solubilizing groups (Fig. 5), the chelate is sufficiently water soluble to be injected. It is... 

Miller, R.A. et al. (1999) In vivo animal studies with gadolinium(III) texaphyrin as a radiation enhancer, Int. J. Radiat. Oncol., Biol., Phys. 45, 981-989. 

Young, S.W. et al. (1994) Preclinical evaluation of gadolinium(III) texaphyrin complex. A new paramagnetic contrast agent for magnetic resonance imaging, Invest Radiol. 29, 330-338. 

Geraldes, C.F. et al. (1995) Nuclear magnetic relaxation dispersion studies of water-soluble gadolinium(III)-texaphyrin complexes, J. Magn. Reson. Imag. 5, 725-729. 

Sessler, J.L. et al. (1999) One-Electron Reduction and Oxidation Studies of the Radiation Sensitizer Gadolinium(III) Texaphyrin (PCI-0120) and Other Water Soluble Metallotexaphyrins, J. Phys. Chem. A 103, 787-794. 

As shown in Fig. 7.6, texaphyrins have a larger cavity than porphyrins so they can form complexes with lanthanide metals such as gadolinium (XCYTRIN ), that enhances the efficacy of treatment for certain brain tumours, and lutetium (LUTRIN ), used as a sensitizer for photodynamic therapy of recurrent breast cancer [17], Crucial to their success is the increased number of donor atoms available as the more lanthanide binding sites that a ligand can satisfy, the more stable the complex. 

The formation of a number of lanthanide texaphyrin complexes has been reported [95]. In all cases, metal insertion and oxidation proceeds smoothly (Scheme 16) [95]. The complexes demonstrate fair water solubility and good stability towards hydrolysis. Detailed kinetic studies of complex 147, for instance indicated that the half-life for decomplexation and/or decomposition of this complex is 37 days in a 1 1 mixture of MeOH H20 (pH7). Thus, it appears that gadolinium (III) complexes of texaphyrins could provide the basis for a new approach to paramagnetic MRI contrast reagent development [95]. 

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